Harvey's Garden

Carbonic anhydrase

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  • Etiology/Pathophysiology
    • A zinc-containing metalloenzyme that catalyzes the rapid, reversible hydration of carbon dioxide (CO2) to carbonic acid (H2CO3), which then dissociates into a proton (H+) and bicarbonate (HCO3-).
    • Reaction: CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3−
    • This reaction is crucial for CO2 transport, acid-base balance, and fluid regulation.
    • Several different isoenzymes exist (e.g., CA-I, CA-II, CA-IV) with varying tissue distribution and activity levels.
  • Key Locations & Functions
    • Red Blood Cells: Facilitates transport of CO2 from peripheral tissues to the lungs. In tissues, CA converts CO2 to H+ and HCO3-. HCO3- is transported out of the RBC in exchange for Cl- (chloride shift). In the lungs, the process is reversed, converting HCO3- back to CO2 for exhalation.
    • Kidney (Proximal Convoluted Tubule - PCT): Essential for reabsorption of filtered bicarbonate. CA is present in the cytoplasm and on the apical brush border. Inhibition leads to ↑ excretion of HCO3-, causing a hyperchloremic, non-anion gap metabolic acidosis and alkaline urine.
    • Eye (Ciliary Body Epithelium): Produces aqueous humor. Inhibition ↓ aqueous humor production, thereby ↓ intraocular pressure.
    • Brain (Choroid Plexus): Involved in the production of cerebrospinal fluid (CSF). Inhibition ↓ CSF production.
    • Stomach (Gastric Mucosa): Provides H+ for gastric acid (HCl) secretion.
    • Pancreas: Aids in the secretion of alkaline pancreatic juice rich in HCO3-.
  • Pharmacology: Carbonic Anhydrase Inhibitors (CAIs)
    • Drug: Acetazolamide is the prototype. Others include dorzolamide (topical for eyes) and methazolamide. These are sulfa drugs.
    • Mechanism: Block the action of carbonic anhydrase.
    • Clinical Uses:
      • Glaucoma: ↓ aqueous humor production (both open-angle and angle-closure).
      • Altitude Sickness: Counteracts respiratory alkalosis by inducing a metabolic acidosis. Also decreases CSF production.
      • Idiopathic Intracranial Hypertension (Pseudotumor Cerebri): ↓ CSF production.
      • Metabolic Alkalosis: Used to correct alkalosis, especially in the setting of diuresis.
      • Urinary Alkalinization: To increase the solubility and excretion of substances like uric acid and cystine, preventing stone formation.
    • Adverse Effects:
      • Hyperchloremic, non-anion gap metabolic acidosis: Due to renal HCO3- wasting.
      • Hypokalemia: Increased K+ excretion in the distal nephron.
      • Promotes Calcium Phosphate Stones: Due to alkaline urine and hypercalciuria.
      • Paresthesias
      • Sulfa Allergy: Contraindicated in patients with known sulfa allergies.
      • Ammonia toxicity: Can worsen hepatic encephalopathy by decreasing urinary excretion of NH3 (converts to NH4+ in acidic urine).

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